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Checkpoint effects and telomere amplification during DNA re-replication in fission yeast
Katie L Mickle, Anna Oliva, Joel A Huberman, Janet Leatherwood
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-119
Abstract: We found that over-expressing a non-phosphorylatable form of the replication-initiation protein, Cdc18 (known as Cdc6 in other eukaryotes), drove re-replication of DNA sequences genome-wide, rather than forcing high level amplification of just a few sequences. Moderate variations in extents of re-replication generated regions spanning hundreds of kilobases that were amplified (or not) ~2-fold more (or less) than average. However, these regions showed little correlation with replication origins used during S phase. The extents and locations of amplified regions in cells deleted for the checkpoint genes encoding Rad3 (ortholog of human ATR and budding yeast Mec1) and Cds1 (ortholog of human Chk2 and budding yeast Rad53) were similar to those in wild-type cells. Relatively minor but distinct effects, including increased re-replication of heterochromatic regions, were found specifically in cells lacking Rad3. These might be due to Cds1-independent roles for Rad3 in regulating re-replication and/or due to the fact that cells lacking Rad3 continued to divide during re-replication, unlike wild-type cells or cells lacking Cds1. In both wild-type and checkpoint-mutant cells, regions near telomeres were particularly susceptible to re-replication. Highly re-replicated telomere-proximal regions (50–100 kb) were, in each case, followed by some of the least re-replicated DNA in the genome.The origins used, and the extent of replication fork progression, during re-replication are largely independent of the replication and DNA-damage checkpoint pathways mediated by Cds1 and Rad3. The fission yeast pattern of telomere-proximal amplification adjacent to a region of under-replication has also been seen in the distantly-related budding yeast, which suggests that subtelomeric sequences may be a promising place to look for DNA re-replication in other organisms.Two key functions of the cell cycle machinery are to ensure (i) that DNA replication is completed before cells enter mitosis and
Need telomere maintenance? Call 911
Sofia Francia, Robert S Weiss, Fabrizio d'Adda di Fagagna
Cell Division , 2007, DOI: 10.1186/1747-1028-2-3
Abstract: Any discontinuity within the DNA double helix is perceived by the cell as a threat to its genetic integrity. Consequently, cells respond promptly to the generation of DNA interruptions by mounting a coordinated set of actions collectively known as the DNA-damage response (DDR) with the intent of arresting cell cycle progression and initiating DNA repair. In higher eukaryotes, the large protein kinases Atm and Atr play central roles in initiating the DDR [1]. Atm responds primarily to double-stranded DNA breaks (DSB). With assistance from the Mrell/Rad50/Nbsl complex, as well as additional mediator and adaptor proteins, Atm phosphorylates and thereby modulates the activity of several substrates involved in cell-cycle control and DNA replication. Bulky DNA lesions, processed DSB, and DNA replication blockage trigger a second DDR pathway involving Atr. These insults lead to the accumulation of single-stranded DNA (ssDNA) coated with the replication protein A (Rpa), a DNA structure that separately attracts Atr and a trimeric complex of Rad9, Rad1, and Hus1 (911) [2]. Atr, in association with its cofactor Atrip, is further stimulated through interactions with Topbpl and, with assistance from the 911 complex and Claspin, phosphorylates and activates the transducer kinase Chkl [3]. Chkl and other Atr targets then mediate a host of DDR outputs, including cell cycle arrest, replication fork stabilization, and DNA repair.The 911 trimer resembles the toroidal sliding clamp proliferating cell nuclear antigen (PCNA) and is loaded onto DNA by a clamp loader composed of Rad17 and replication factor C (RFC) subunits [4]. While many DDR factors function exclusively in DNA damage signaling, the 911 complex also directly participates in DNA metabolism. The checkpoint clamp physically associates with several factors required for base excision repair (BER) [5-11] and additionally interacts with translesion DNA polymerases [12,13]. 911 function is also required for homologous recombinati
Genetic Variation in Telomere Maintenance Genes, Telomere Length and Breast Cancer Risk  [PDF]
Jing Shen, Mary Beth Terry, Yuyan Liao, Irina Gurvich, Qiao Wang, Ruby T. Senie, Regina M. Santella
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044308
Abstract: Background Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses. Methods We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model. Results We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use <5yrs and 0.59 (SD = 0.24) for HRT use ≥5yrs after adjusting for age of blood donation and race and ethnicity. Conclusions We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.
Telomere Reprogramming and Maintenance in Porcine iPS Cells  [PDF]
Guangzhen Ji, Weimin Ruan, Kai Liu, Fang Wang, Despoina Sakellariou, Jijun Chen, Yang Yang, Maja Okuka, Jianyong Han, Zhonghua Liu, Liangxue Lai, Sarantis Gagos, Lei Xiao, Hongkui Deng, Ning Li, Lin Liu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074202
Abstract: Telomere reprogramming and silencing of exogenous genes have been demonstrated in mouse and human induced pluripotent stem cells (iPS cells). Pigs have the potential to provide xenotransplant for humans, and to model and test human diseases. We investigated the telomere length and maintenance in porcine iPS cells generated and cultured under various conditions. Telomere lengths vary among different porcine iPS cell lines, some with telomere elongation and maintenance, and others telomere shortening. Porcine iPS cells with sufficient telomere length maintenance show the ability to differentiate in vivo by teratoma formation test. IPS cells with short or dysfunctional telomeres exhibit reduced ability to form teratomas. Moreover, insufficient telomerase and incomplete telomere reprogramming and/or maintenance link to sustained activation of exogenous genes in porcine iPS cells. In contrast, porcine iPS cells with reduced expression of exogenous genes or partial exogene silencing exhibit insufficient activation of endogenous pluripotent genes and telomerase genes, accompanied by telomere shortening with increasing passages. Moreover, telomere doublets, telomere sister chromatid exchanges and t-circles that presumably are involved in telomere lengthening by recombination also are found in porcine iPS cells. These data suggest that both telomerase-dependent and telomerase-independent mechanisms are involved in telomere reprogramming during induction and passages of porcine iPS cells, but these are insufficient, resulting in increased telomere damage and shortening, and chromosomal instability. Active exogenes might compensate for insufficient activation of endogenous genes and incomplete telomere reprogramming and maintenance of porcine iPS cells. Further understanding of telomere reprogramming and maintenance may help improve the quality of porcine iPS cells.
Innovation in Preserving and Conserving Book Heritage  [cached]
Armida Batori
Liber Quarterly : The Journal of European Research Libraries , 2003,
Abstract: The Istituto Centrale di Patologia del Libro (ICPL) is a branch of the Italian Ministry of Cultural Heritage and Activities whose work is chiefly concerned with research and specialized training in the conservation and restoration of library materials. The Institute was founded in 1938 during a truly propitious period for cultural heritage in general. It was in 1939, in fact, that Law No. 1089 - 'The Safeguarding of Articles of Artistic and Historic Interest' - was issued, and in the same year the Istituto Centrale di Restauro was established under the direction of Cesare Brandi.
A Novel Checkpoint and RPA Inhibitory Pathway Regulated by Rif1  [PDF]
Yuan Xue,Michael D. Rushton,Laura Maringele
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002417
Abstract: Cells accumulate single-stranded DNA (ssDNA) when telomere capping, DNA replication, or DNA repair is impeded. This accumulation leads to cell cycle arrest through activating the DNA–damage checkpoints involved in cancer protection. Hence, ssDNA accumulation could be an anti-cancer mechanism. However, ssDNA has to accumulate above a certain threshold to activate checkpoints. What determines this checkpoint-activation threshold is an important, yet unanswered question. Here we identify Rif1 (Rap1-Interacting Factor 1) as a threshold-setter. Following telomere uncapping, we show that budding yeast Rif1 has unprecedented effects for a protein, inhibiting the recruitment of checkpoint proteins and RPA (Replication Protein A) to damaged chromosome regions, without significantly affecting the accumulation of ssDNA at those regions. Using chromatin immuno-precipitation, we provide evidence that Rif1 acts as a molecular “band-aid” for ssDNA lesions, associating with DNA damage independently of Rap1. In consequence, small or incipient lesions are protected from RPA and checkpoint proteins. When longer stretches of ssDNA are generated, they extend beyond the junction-proximal Rif1-protected regions. In consequence, the damage is detected and checkpoint signals are fired, resulting in cell cycle arrest. However, increased Rif1 expression raises the checkpoint-activation threshold to the point it simulates a checkpoint knockout and can also terminate a checkpoint arrest, despite persistent telomere deficiency. Our work has important implications for understanding the checkpoint and RPA–dependent DNA–damage responses in eukaryotic cells.
Mathematical model of alternative mechanism of telomere length maintenance  [PDF]
Richard Kollár,Katarina Bodova,Jozef Nosek,Lubomir Tomaska
Quantitative Biology , 2014, DOI: 10.1103/PhysRevE.89.032701
Abstract: Biopolymer length regulation is a complex process that involves a large number of subprocesses acting simultaneously across multiple spatial and temporal scales. An illustrative example important for genomic stability is the length regulation of telomeres---nucleo-protein structures at the ends of linear chromosomes. Maintenance of telomeres is often facilitated by the enzyme telomerase but, particularly in telomerase-free systems, the maintenance of chromosomal termini depends on alternative lengthening of telomeres (ALT) mechanisms mediated by recombination. Various linear and circular DNA structures were identified to participate in ALT, however, dynamics of the whole process is still poorly understood. We propose a chemical kinetics model of ALT with kinetic rates systematically derived from the biophysics of DNA diffusion and looping. The reaction system is reduced to a coagulation-fragmentation system by quasi-steady state approximation. The detailed treatment of kinetic rates yields explicit formulae for expected size distributions of telomeres that demonstrate the key role played by the J-factor, a quantitative measure of bending of polymers. The results are in agreement with experimental data and point out interesting phenomena: an appearance of very long telomeric circles if the total telomere density exceeds a critical value (excess mass) and a nonlinear response of the telomere size distributions to the amount of telomeric DNA in the system. The results can be of general importance for understanding dynamics of telomeres in telomerase-independent systems as this mode of telomere maintenance is similar to the situation in tumor cells lacking telomerase activity. Furthermore, due to its universality, the model may also serve as a prototype of an interaction between linear and circular DNA structures in various settings.
Maintenance Management Framework for Conservation of Heritage Buildings in Malaysia  [cached]
Arazi Idrus,Faris Khamidi,Mahmoud Sodangi
Modern Applied Science , 2010, DOI: 10.5539/mas.v4n11p66
Abstract: Despite the enactment of the National Heritage Act and establishment of the National Heritage Department in Malaysia, many heritage buildings still remain in poor conditions with signs of serious building defects threatening their survival because Legislations related to heritage buildings in the country do not sufficiently address the issue of maintenance and its management in the conservation of heritage buildings thereby resulting to poor maintenance management practices which eventually lead to deterioration of the buildings. More so, despite the rhetoric of the significance of maintenance management in the conservation of heritage buildings in Malaysia, there is still inadequate guidance about how maintenance should be envisaged, managed and integrated with other key management activities in the context of heritage building conservation. This paper is part of an ongoing research aimed at developing a maintenance management framework for conservation of heritage buildings in Malaysia. The proposed conceptual framework will provide a holistic guidance and understanding of the maintenance management practices to be adopted in the conservation of heritage buildings in Malaysia. This would enable custodians of heritage buildings in Malaysia to evaluate their maintenance management practices in relation to best practices and be able to re-position their maintenance management approaches to best practice standard.
Preserving Intangible Heritage in Japan: the Role of the Iemoto System
Voltaire Garces Cang
International Journal of Intangible Heritage , 2008,
Abstract: Many forms of Japan’s intangible heritage, including its three ‘Masterpieces of the Oral and Intangible Heritage of Humanity’, are headed by hereditary masters called iemoto. This paper examines the iemoto system as it relates to the exclusive rights of the iemoto. Through case studies taken mainly from the traditions of the tea ceremony, Nˉogaku, and Kabuki, the state of Japanese art traditions under the said system is also discussed.Although the iemoto system is shown to be authoritarian in various ways, it has also played a crucial role in the preservation of intangible heritage in Japan.
Rif1 Supports the Function of the CST Complex in Yeast Telomere Capping  [PDF]
Savani Anbalagan,Diego Bonetti,Giovanna Lucchini,Maria Pia Longhese
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002024
Abstract: Telomere integrity in budding yeast depends on the CST (Cdc13-Stn1-Ten1) and shelterin-like (Rap1-Rif1-Rif2) complexes, which are thought to act independently from each other. Here we show that a specific functional interaction indeed exists among components of the two complexes. In particular, unlike RIF2 deletion, the lack of Rif1 is lethal for stn1ΔC cells and causes a dramatic reduction in viability of cdc13-1 and cdc13-5 mutants. This synthetic interaction between Rif1 and the CST complex occurs independently of rif1Δ-induced alterations in telomere length. Both cdc13-1 rif1Δ and cdc13-5 rif1Δ cells display very high amounts of telomeric single-stranded DNA and DNA damage checkpoint activation, indicating that severe defects in telomere integrity cause their loss of viability. In agreement with this hypothesis, both DNA damage checkpoint activation and lethality in cdc13 rif1Δ cells are partially counteracted by the lack of the Exo1 nuclease, which is involved in telomeric single-stranded DNA generation. The functional interaction between Rif1 and the CST complex is specific, because RIF1 deletion does not enhance checkpoint activation in case of CST-independent telomere capping deficiencies, such as those caused by the absence of Yku or telomerase. Thus, these data highlight a novel role for Rif1 in assisting the essential telomere protection function of the CST complex.
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